The eukaryotic stress response involves translational suppression of non-housekeeping proteins, and the sequestration of unnecessary mRNA transcripts into stress granules (SGs). This process is dependent on mRNA binding proteins, such as T-cell intracellular antigen (TIA-1), that interact with unnecessary mRNA transcripts through prion and poly-glutamine like domains, and their aggregation mirrors that of proteins linked to neurodegenerative diseases. Neurodegenerative-linked proteins Huntingtin, PrP prion protein, and TDP-43 have all been shown to associate with SGs, but no such investigation has been done with respect to Alzheimer's disease (AD) pathogenic proteins A or tau. Our preliminary data indicates that SGs are a novel pathology related to AD that colocalize with pathogenic tau in human AD brain tissue. Immunohistochemical time course data obtained using Tg JNPL3 mice expressing P301L mutant tau suggests that SGs track with disease severity, and may provide a good biomarker of disease progression. Cell type localization of SGs indicate that early in the disease progression SGs are present in glial cells, and their disappearance in these cell types correlates with activation of microglia and astrocytosis, suggesting that SGs may play a role in regulating the immune response early in the disease process. The work in this project will address key questions about the mechanisms underlying SG pathology in AD using murine AD models and primary cultures to determine the relationship between SG, A, and tau pathology. SGs are also known to play a critical role in regulating the inflammatory response in the periphery, but this has not been addressed in the CNS. The last portion of this proposal will focus on role of SGs in the microglial response to A stimulation, focusing on the regulation of cytokine expression and release using primary microglial cultures from Tg TIA-1 knockout mice. The scientific community continues to elucidate the pathophysiology of AD. Our findings indicate SGs as a novel type of pathology that occurs in AD that develops in parallel with A and tau pathology, complements studies of A and tau, and also potentially provides insight into the inflammatory process in AD. Understanding the role of SGs in AD may provide new insight into the relationship between toxic A species, NFTs, and neuronal death and dysfunction, which remains an obstacle in our ability to understand the complexity of the disease process. This research could provide novel biomarkers for examining the progression of neurodegeneration, and also potentially provide novel pathological targets that are responsive to therapeutic intervention.